Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disease and one of the leading causes of cognitive disability in the elderly. Sporadic Alzheimer's disease (SAD) patients make up the majority of AD cases but the cause of this form of the disease is unknown. However, a number of risk factors, other than aging alone, have been identified that impact the development of AD. Low oxygen levels, or hypoperfusion is a common element among many factors that lead to increased risk of AD. These include ischemic stroke, oligemic incident, traumatic brain injury, hypoxia, cardiac arrest, hyperemia and cerebral blood pressure that is excessively lower or higher than the periphery. Here we propose to study the impact of altered cerebral blood flow on the development of AD-related pathology and cognitive decline in a transgenic mouse model of the disease. Clinically, it has been shown that both ischemic and oligemic episodes increase the risk for developing AD at a later date. Animal models of ischemia have been shown to increase APR and amyloid-beta pathology while cerebrovascular disease and ischemia have both been associated with a decreased level of tau pathology in AD patients (Esiri et al., 1999;Goulding et al., 1999;Breteler, 2000). By modeling both oligemia and ischemia, we are able to model the effects of mild blood flow intrusions, such as transient ischemic attacks, cerebrovascular disease and atherosclerosis, as well as the more severe insults such as stroke and heart attack and assess the differential effects that these may have on disease progression. Further, modeling these diseases in a mouse model that develops both Ad and tau pathologies, puts us in a unique position to identify the molecular changes that occur following these insults that alter Ad and tau progression. Public Health Relevance: As the majority of AD patients suffer from co-morbid conditions, it is imperative to begin to dissect their interactions in an experimental setting. This project is designed to examine the interaction between ischemia and AD pathology development and cognitive decline.